Researchers demonstrated CRISPR–Cas3 as a distinct genome‑editing modality for transthyretin (TTR) amyloidosis, producing long directional deletions that abolished TTR expression in vitro and substantially reduced serum TTR in vivo. A single lipid‑nanoparticle dose achieved roughly 48.7% hepatic editing and an 80.1% reduction in circulating TTR in treated mice. The study contrasted Cas3’s large‑deletion profile and lower off‑target footprint with Cas9’s indel‑focused edits and reported deletions up to 75 kb in vitro and 21 kb in vivo. Authors positioned Cas3 as a promising alternative for systemic proteinopathies where durable gene disruption is desirable; delivery and long‑term safety will determine clinical translatability relative to existing LNP‑Cas9 therapeutics such as NTLA‑2001.